Claggett, Brian

Background This study aims to characterize right ventricular dysfunction (RVD) in heart failure (HF) with preserved ejection fraction and understand the cumulative prognostic value of abnormal RV echocardiographic parameters in HF with preserved ejection fraction. Methods and Results Data from 809 patients in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin‐Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction) echocardiographic substudy (55% women, mean age 74±8 years) were analyzed. Correlates of RVD (defined as tricuspid annular plane systolic excursion <1.7 cm, fractional area change <35% or absolute RV free wall longitudinal strain <20%) were identified using multivariable logistic regression models. We further assessed the prognostic value of the number of abnormal RV parameters (0, 1, ≥2) on total HF hospitalizations (HFH) and cardiovascular death, total HFH, first HFH or cardiovascular death, all‐cause death, and cardiovascular death. RVD was identified in 461 (57%) patients. Correlates of RVD included older age, higher heart rate, atrial fibrillation/flutter, greater left ventricle wall thickness, higher N‐terminal pro‐B‐type natriuretic peptide levels, lower systolic blood pressure, and lower left ventricle absolute global longitudinal strain. These results were consistent across sexes, except atrial fibrillation/flutter and LV wall thickness, which were associated with a higher risk of RVD in men but not in women. Participants with ≥2 abnormal RV parameters had a significantly higher adjusted risk of total HFH and cardiovascular death (rate ratio, 2.13 [95% CI, 1.13–4.01]), first HFH or cardiovascular death, all‐cause death, and cardiovascular death. Conversely, an isolated abnormal RV parameter was not associated with a worse outcome. Conclusions RV measures may underestimate the burden of RVD in HF with preserved ejection fraction when considered in isolation. Clinicians should consider multiple dimensions to comprehensively assess RV function in patients with HF with preserved ejection fraction.

Abstract Aims To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON-HF trial. Methods and results A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: &lt;65 years (n = 825), 65–74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory. The primary composite outcome was total HF hospitalizations and cardiovascular (CV) death. Older patients were more likely to experience primary composite outcomes (compared to patients &lt;65 years, adjusted rate ratio [aRR] for ≥75 years: 1.39, 95% confidence interval [CI] 1.21–1.61), total HF hospitalization (aRR 1.27, 95% CI 1.09–1.49), and CV death (adjusted hazard ratio [aHR] 2.04, 95% CI 1.44–2.87). Age did not modify the effect of sacubitril/valsartan compared to valsartan on primary composite endpoint (pinteraction = 0.79) in the overall population or in those with LVEF ≤57%. Older adults randomized to sacubitril/valsartan were more likely to develop hypotension compared to those receiving valsartan (pinteraction = 0.026). Older patients had smaller left ventricular chamber sizes, higher LVEF, and were more likely to have abnormal measures of diastolic function. Conclusion Older patients with HF with preserved ejection fraction had higher event rates than younger patients, more adverse events overall, and more hypotension when treated with sacubitril/valsartan; however, the treatment benefits of sacubitril/valsartan were retained in older patients.

BACKGROUND: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: At baseline, cognitive function was normal (MMSE score 28–30) in 1809 of 2895 patients (62.5%), borderline (score 24–27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemic attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first heart failure hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06–1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21–2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was −0.05 (SE, 0.07); the corresponding change in the valsartan group was −0.04 (0.07). The mean between-treatment difference at week 96 was −0.01 (95% CI, −0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

Abstract Aims Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population. Methods and results We assessed two-dimensional speckle-tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON-HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS &lt;16%. Impaired GLS was significantly associated with higher values of circulating baseline N-terminal pro-B-type-natriuretic peptide. After a median follow-up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02–1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction &gt;0.1). Conclusions In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF.

Introduction: Impaired tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC) and right ventricular free wall longitudinal strain (RVFWLS) have been individually associated with a worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF). However, these parameters measure different aspects of RV function and understanding their cumulative effect may provide insights into the overall impact of RV dysfunction (RVD) in HFpEF patients. Goal: Assess the association between the number of echocardiographic RVD parameters and clinical outcomes. Methods: Patients from the echocardiographic sub-study of the PARAGON-HF trial with adequate image quality (N=809, 53% women, mean age 74±8 years) were categorized based on the number of measures of RVD, which included TAPSE <1.7 cm, FAC <35% or RVFWLS <20% (absolute value). Associations with total HF hospitalizations (HFH) and CV death, total HFH alone, first HFH or CV death, all-cause death and CV death were assessed by Groups, after accounting for confounders. Results: A total of 348 patients (43%) in Group 0 (no abnormal parameter), 355 (44%) in Group 1 (one abnormal parameter) and 106 (13%) in Group 2 (two or more abnormal parameters) were identified. After multivariable adjustment ( Table ), Group 2 was significantly associated with an increased risk of total HFH and CV death (RR 2.13, 95%CI 1.13-4.01), first HFH or CV death (RR 2.07, 95%CI 1.15-3.73), all-cause death (RR 2.61, 95%CI 1.19-5.74) and CV death (RR 3.08, 95%CI 1.14-8.31). The treatment effect of sacubitril/valsartan for total HFH and CV death was not modified by RVD Group (p-value for interaction=0.94). Conclusions: The presence of two or more RVD parameters was associated with a significantly worse prognosis, while an isolated RVD measure was not. These findings suggest that a more comprehensive approach to assessment of RV function may have better prognostic value in HFpEF.

Introduction: Right ventricular dysfunction (RVD) is a major prognostic factor in patients with heart failure with preserved ejection fraction (HFpEF), however determinants of RVD in HFpEF are not well described. Although sex-specific mechanisms have been incriminated in the development of HFpEF, it is unclear whether this is also true for RVD. Goals: (1) Assess the prevalence of RVD (defined as a tricuspid annular plane systolic excursion [TAPSE] <1.7 cm, a fractional area change [FAC] <35% or a RV free wall longitudinal strain [RVFWLS] <20%, absolute value) in patients with HFpEF; (2) identify determinants of RVD, overall and according to sex, in patients with HFpEF. Methods: We used data from patients enrolled in the echocardiographic sub-study of the PARAGON-HF trial with adequate image quality (N=809, 53% women, mean age 74±8 years). Determinants of RVD, in the whole study population and according to sex, were identified using a multivariable logistic regression model. Results: There were 461 patients (57%) with RVD. After multivariable adjustment, RVD was cross-sectionally associated with a history of atrial fibrillation of flutter (AFF), older age, higher heart rate, greater LV mean wall thickness and higher NT-proBNP values. Systolic blood pressure and LV global longitudinal strain (absolute value) showed an inverse association ( Figure ). These results were consistent between men and women, except for AFF and LV mean wall thickness, which were associated with a greater likelihood of RVD in men (OR 2.46, 95%CI 1.33-4.56, OR 1.61, 95%CI 1.18-2.21 respectively) but not in women (OR 0.99, 95%CI 0.58-1.68, OR 0.90 95%CI 0.69-1.17 respectively, p-values for interaction=0.028 and 0.006). Conclusions: RVD was highly prevalent in our study population. Determinants of RVD included AFF, LV remodeling and systolic impairment, and increased NT-proBNP levels. Differences between men and women suggest gender-specific mechanisms in the development of RVD in HFpEF.

Introduction: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Goal: To identify serum proteins associated with risk for HF hospitalization (HFH) and cardiovascular (CV) death in patients with HFpEF, including proteins with differential associations with clinical outcomes in HFpEF compared to HFrEF. Methods: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF in the PARAGON-HF trial using a modified aptamer proteomic assay. Baseline protein concentrations significantly associated with total HFH and CV death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared to 2515 patients with HFrEF from the PARADIGM-HF and ATMOSPHERE trials. Results: We identified 288 proteins to be robustly associated with the risk of HFH and CV death (335 events over an average of 2.7 years of follow-up) in a HFpEF trial population. Proteins most strongly related to HFpEF outcomes included B2M, TIMP1, SERPINA4, and SVEP1 ( Figure ). Protein-outcome associations in patients with HFpEF did not markedly differ compared to HFrEF. Just 3 proteins (APOE, RTF1, and VWF) were differentially associated with outcomes between the HF subtypes (FDR <0.05). A proteomic risk score derived in HFpEF patients was not superior to a previous proteomic score derived in HFrEF nor to clinical risk factors, NT-proBNP, or high-sensitivity cardiac troponin. Conclusions: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis. SVEP1, a cell adhesion protein recently identified as a HFrEF prognosis biomarker, also strongly predicted risk in HFpEF. Our results demonstrate substantial similarities in serum proteomic risk markers across the EF spectrum.